Abstract
Background
Oxaliplatin, a key agent used for managing metastatic colorectal cancer (mCRC), is often discontinued due to cumulative toxicity. Its reintroduction in later treatment lines remains a common clinical practice, despite the absence of robust prospective trials supporting this therapeutic strategy. This study aimed to evaluate the efficacy of oxaliplatin rechallenge in refractory mCRC and to identify patient characteristics predictive of improved outcomes with this approach.
Patients and methods
We retrospectively analyzed patients treated with oxaliplatin in the third- or fourth-line setting at Vall d’Hebron Hospital between 2015 and 2021. Outcomes included overall response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS). Patients achieving median PFS >6 months were classified as best-responders. Factors affecting PFS were analyzed with a Cox regression model. Amplicon-seq analysis of 61 genes was carried out using Illumina technology.
Results
Of 735 patients receiving third- or fourth-line treatment, 102 (14%) received oxaliplatin retreatment (69% in third line; 31% in fourth line). Median PFS was 4.0 months (95% CI 3.29-5.03 months), with an ORR of 12% and DCR of 39%. Twenty-eight patients (27%) were best-responders. Predictors of efficacy included response to first-line oxaliplatin, planned oxaliplatin discontinuation, and an oxaliplatin-free interval of at least 22.0 months. No significant associations were identified between molecular alterations and prognostic subgroups.
Conclusions
Oxaliplatin-based reintroduction therapy is a viable strategy in mCRC, particularly for patients with a favorable prior response and prolonged oxaliplatin-free intervals. However, identifying more precise biomarkers is essential to improve patient selection and maximize treatment efficacy.
Key words: oxaliplatin, rechallenge, reintroduce, refractory, metastatic colorectal cancer (mCRC)
Highlights
-
•
Oxaliplatin retreatment is common in mCRC, despite limited prospective evidence.
-
•
This study involved 102 patients with mCRC, who received oxaliplatin retreatment as third- or fourth-line therapy at Vall d’Hebron Hospital.
-
•
Median PFS was 4.0 months; ORR 12% and DCR 39% in retreatment patients.
-
•
Better outcomes with prior response, planned stop, and ≥22-month free oxaliplatin interval.
-
•
No genomic predictors found; need for biomarkers to guide rechallenge strategy.
Introduction
The therapeutic backbone of first- and second-line treatments for metastatic colorectal (mCRC) cancer is well established. Patients typically receive fluoropyrimidine-based chemotherapy, combined sequentially with oxaliplatin and/or irinotecan, in any order, along with vascular endothelial growth factor-targeted agents and, for RAS wild-type tumors, epidermal growth factor receptor (EGFR) inhibitors.1,2 Progression on these therapies defines refractory disease, although many patients remain eligible for further treatment.
Until recently, therapeutic options for patients in this refractory setting, outside of clinical trials, were limited, with retreatment using chemotherapeutic agents like oxaliplatin commonly employed in routine practice.3 Retreatment with oxaliplatin-based therapies can be classified as reintroduction or rechallenge, depending on the clinical context. Reintroduction typically involves restarting oxaliplatin after a planned discontinuation in patients whose tumors have not progressed during the initial treatment, often due to cumulative toxicity. In contrast, rechallenge refers to its reuse after disease progression, raising concerns about resistance and reduced efficacy.4, 5, 6
In recent years, the strategy of discontinuing oxaliplatin after six to eight cycles during first-line therapy and continuing with maintenance treatment has become widely adopted and is now endorsed by clinical guidelines.1,2,7, 8, 9 This approach provides a rationale for oxaliplatin reintroduction in later lines.
Despite its frequent use in clinical practice, the reintroduction or rechallenge of oxaliplatin in later treatment lines is not supported by robust prospective evidence.10, 11, 12, 13 Most available data come from retrospective studies or subgroup analyses within larger trials, often limited by heterogeneous populations and insufficient statistical power.4, 5, 6 As a result, patient selection, optimal timing, and clinical benefit remain uncertain. Moreover, in recent years, treatment options for these patients have expanded significantly. Beyond the reintroduction of chemotherapeutic agents like oxaliplatin, novel strategies have emerged, including EGFR rechallenge in patients with RAS wild-type tumors, combinations like trifluridine/tipiracil (FTD/TPI) with or without bevacizumab, antiangiogenic agents such as regorafenib and fruquintinib, and targeted therapies for patients with clinically actionable molecular alterations.1,2,14, 15, 16, 17 This shift in available treatments has made selecting the optimal therapeutic strategy more challenging, emphasizing the need for robust data on these options to guide the choice of the most appropriate approach.
To enhance our understanding of this clinical scenario, we conducted a retrospective study aimed at identifying subgroups of patients with mCRC who may derive meaningful benefit from oxaliplatin-based retreatment in the refractory setting.
Patients and methods
Patient selection
This retrospective observational cohort study included patients with pathologically confirmed metastatic colorectal adenocarcinoma treated at Vall d’Hebron Hospital between 1 January 2015 and 31 December 2021. All patients retreated with oxaliplatin (rechallenge or reintroduction) for third- or fourth-line refractory mCRC after first- or second-line oxaliplatin-based treatment were included. The regimens in the retreatment setting were mFOLFOX6 or XELOX, depending on clinical decision. Patients who received oxaliplatin in the adjuvant setting but relapsed within 6 months after completing treatment were considered to have been treated with oxaliplatin in the first-line metastatic setting. Patients were identified through the institutional electronic medical records system at Vall d’Hebron Hospital. Additionally, pharmacy dispensing records were reviewed to confirm the administration of oxaliplatin in the rechallenge or reintroduction setting. Data collection was carried out retrospectively by trained data curators with expertise in oncology research. To ensure accuracy, data entry was independently verified by a second reviewer.
Study design and patient subgroups
The aim of this study was to identify characteristics associated with benefit from oxaliplatin retreatment. The selection of clinical variables for uni- and multivariable modeling was based on a combination of prior literature, clinical relevance, and data availability within the institutional database. Key variables, such as prior exposure to oxaliplatin, treatment-free interval, response to rechallenge, and survival outcomes, were chosen based on their established prognostic value in mCRC and their role in guiding treatment decisions.
Patients were classified into three clinical groups according to characteristics, as previously reported: best prognostic characteristics defined as ≥18 months since metastatic disease onset, less than three metastatic sites and absence of liver metastases; good prognostic characteristics defined as ≥18 months since metastatic disease onset, less than three metastatic sites and presence of liver metastasis; and poor prognostic characteristics defined as <18 months since metastatic disease onset and/or three or more metastatic sites.16
Patients who achieved >6 months of median progression-free survival (PFS) were defined as best-responders. Tumor molecular profiling was carried out using a Vall d’Hebron Institute of Oncology-designed Amplicon-seq panel. Amplicon-based next-generation sequencing (amplicon-seq) is a targeted sequencing approach that amplifies specific genomic regions of interest using multiplex PCR, enabling high-depth analysis of low-input DNA from formalin-fixed paraffin-embedded tumor samples or circulating tumor DNA and sequenced on an Illumina platform following standard protocols. The 61-gene panel used in this study covers key oncogenic drivers and resistance-associated mutations relevant to mCRC.
Study endpoints
Outcomes analyzed in all patients undergoing oxaliplatin rechallenge were overall response rate (ORR), disease control rate (DCR), and median PFS. Efficacy endpoints were assessed based on medical records and according to Response Evaluation Criteria in Solid Tumors.
PFS was analyzed according to the reason for discontinuation of oxaliplatin in first-line setting [progression of disease (PD) versus planned discontinuation versus toxicity]; line of treatment (third versus fourth line); response status [PD versus partial response versus stable disease versus complete response (CR)]. The addition of bevacizumab to the first-line oxaliplatin-based regimen and the retreatment subgroup was analyzed.
Statistical analysis
Patient characteristics at baseline were analyzed using descriptive statistics. Survival curves were generated using the Kaplan–Meier method, and differences between groups were calculated using the log-rank test. Cox proportional hazards models with a stepwise procedure were used to estimate the hazard ratio (HR) and the corresponding 95% confidence interval (CI).18 A multivariate Cox proportional hazards model was used to identify factors associated with PFS estimating HR and 95% CI, while verifying the proportional hazards assumption.18 In parallel, a logistic regression model was applied to define variables associated with long PFS (best-responders), categorizing patients based on a predefined cutoff. Variables with P < 0.1 in univariate analysis and those considered clinically relevant were included in the multivariable model. Oxaliplatin-free intervals were calculated from initial oxaliplatin stop to oxaliplatin retreatment start. All analyses were conducted with R statistical software (version R 4.4.3).
Results
Patient characteristics
A total of 735 mCRC patients underwent third- and fourth-line treatment in our institution. Of them, 102 (14%) patients received an oxaliplatin-based regimen and were included in the analysis. Median age was 57 years [interquartile range (IQR) 32-77 years], 56 (55%) were male and 77 (75%) had left-sided disease. Most patients, (n = 85; 83%), were diagnosed with metastatic disease. Regarding mismatch repair status, 78 (76%) patients were microsatellite stable (MSS), whereas only 1 (1%) patient was microsatellite instability-high (MSI-H) and in 23 (23%) patients mismatch repair status was unknown. KRAS mutations were identified in 59 (58%) patients, NRAS mutations in 4 (4%) patients, and BRAF mutations in 3 (3%) patients. Clinicopathological characteristics are summarized in Table 1. Patients received a median of 5 (IQR 4-7) systemic lines of treatment. In the first-line setting, 85 (83%) patients responded to oxaliplatin-based treatment, with a median PFS of 11.1 months (95% CI 10.2-13.9 months). The median number of cycles in the first-line setting was 10 (IQR 8-12) and 57 (56%) of patients also received a monoclonal antibody in this context. Oxaliplatin treatment was discontinued in 51 (50%) patients of the cohort as per the planned therapeutic approach, in 30 (29%) patients due to toxicity, and in 18 (18%) patients because of disease progression. mFOLFOX6 was the regimen more indicated in oxaliplatin retreatment setting, in 94 (92%) patients.
Table 1.
Baseline patients’ demographic and disease characteristics
| Variable | Patients, n (%) N = 102 |
|---|---|
| Median age (IQR), years | 57 (32-77) |
| Sex | |
| Female | 46 (45) |
| Male | 56 (55) |
| Tumor location | |
| Left | 77 (75) |
| Right | 25 (25) |
| Stage at diagnosis | |
| I | 3 (3) |
| II | 6 (6) |
| III | 8 (8) |
| IV | 85 (83) |
| Sites of metastasis | |
| Liver | 73 (72) |
| Lung | 44 (43) |
| Peritoneum | 28 (27) |
| Lymph nodes | 15 (15) |
| MSI status | |
| MSI-H | 1 (1) |
| MSI-L/MSS | 78 (76) |
| Unknown | 23 (23) |
| KRAS status | |
| Mutated | 59 (58) |
| Wild-type | 40 (39) |
| Unknown | 3 (3) |
| NRAS status | |
| Mutated | 4 (4) |
| Wild-type | 78 (76) |
| Unknown | 20 (20) |
| Bevacizumab in first line | |
| Yes | 40 (39) |
| No | 62 (61) |
| Median oxaliplatin-free interval, months | 17.2 (13.0-23.2) |
| Reason stopping first-line oxaliplatin | |
| Planned | 51 (50) |
| Toxicity | 30 (29) |
| Disease progression | 18 (18) |
| Unknown | 3 (3) |
| Oxaliplatin retreatment line | |
| Third line | 70 (69) |
| Fourth line | 32 (31) |
| Regimen retreatment line | |
| XELOX | 8 (8) |
| mFOLFOX6 | 94 (92) |
IQR, interquartile range; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable.
Progression-free survival in the oxaliplatin retreatment setting
Oxaliplatin retreatment was administered as third-line therapy in 70 (69%) patients and as fourth-line therapy in 32 patients (31%). Most of the patients, 92 (91%), received oxaliplatin as a reintroduction strategy, whereas only 3 (3%) underwent rechallenge; in 6 (6%) patients retreatment/rechallenge status was unknown. The median oxaliplatin-free interval was 17.2 months (95% CI 13.0-23.2 months).
Median PFS in the overall cohort was 4.0 months (95% CI 3.3-5.0 months) (Figure 1A), with a DCR of 39%, and a 12% ORR. Median overall survival (OS) was 13.5 months (95% CI 11.1-16.1 months) (Figure 1B). Median PFS with third- and fourth-line treatment was 4.5 months (95% CI 3.2-5.7 months) and 3.7 months (95% CI 3.0-4.4 months), respectively. Patients with triple wild-type tumors presented numerically longer median PFS of 5.7 months (95% CI 3.7-8.0 months) when compared with those with BRAF or RAS mutation (3.6 months, 95% CI 7.2-4.1 months) (HR 1.45, 95% CI 1-2.2, P = 0.08).
Figure 1.
Kaplan–Meier analysis of progression-free survival (PFS). (A) Kaplan–Meier analysis of overall survival (OS). (B) PFS according to bevacizumab administration or no bevacizumab administration in the first-line and retreatment settings, respectively. (C) PFS in the retreatment context according to the reason for oxaliplatin discontinuation (planned; disease progression; toxicity). (D) PFS according to the median oxaliplatin-free interval of ≤17.2 or >17.2 months. (E) PFS according to median of oxaliplatin-free interval ≤22.0 or >22.0 months. (F) Median PFS is shown. B, bevacizumab administration; NB, no bevacizumab administration.
In the overall cohort, 40 (39%) patients received bevacizumab with oxaliplatin in the first-line setting, and 49 (49%) were treated with bevacizumab during oxaliplatin retreatment. Median PFS was 6.5 months (95% CI 4.1-9.2 months) in patients who received bevacizumab in the retreatment setting compared with 3.0 months (95% CI 2.0-5.5 months) in patients who had never received bevacizumab (HR 0.51, 95% CI 0.3-0.7, P = 0.001) (Figure 1C).
Analysis of PFS according to response to first-line treatment showed median PFS was 5.7 months [95% CI 3.0 months to not reached (NR)] for patients who achieved CR (3 patients, 3%) versus 1.7 months (95% CI 1.45 months to NR) for patients with a best response of PD (49 patients, 49%). Median PFS for patients who discontinued oxaliplatin per management plan was 5.0 months (95% CI 4.0-7.3 months) compared with 3.3 months (95% CI 1.8-9.5 months) for those with PD as reason for treatment discontinuation, and 3.2 months (95% CI 2.3-4.4 months) for patients with toxicity (Figure 1D).
Median PFS was 3.8 months (95% CI 2.5-5.0 months) for patients with an oxaliplatin-free interval below the median cutoff of 17.2 months, compared with median PFS of 4.2 months (95% CI 3.7-7.8 months) for patients with an oxaliplatin-free interval above the median cutoff of 17.2 months (HR 1.45, 95% CI 0.96-2.20 months, P = 0.08) (Figure 1E). An exploratory analysis identified the optimal cutoff for the oxaliplatin-free interval as 22 months to see benefit in the oxaliplatin retreatment setting. Median PFS was 5.7 months (95% CI 3.9-8.3 months) for patients with an interval >22 months compared with 3.6 (95% CI 2.5-4.5 months) for patients with an interval of ≤22 months (HR 1.68, 95% CI 1.09-2.59 months, P = 0.01) (Figure 1F).
In a multivariate analysis of PFS, determinants of favorable outcome were left-sided disease (P = 0.009), administration of bevacizumab in the refractory setting (P = 0.001) and in first line (P = 0.013), and not receiving bevacizumab in first-line treatment (P = 0.013) (Table 2).
Table 2.
Factors predictive of progression-free survival in patients receiving oxaliplatin retreatment (n = 99): Cox-univariate and multivariate analyses
| Variable | Median PFS | HR univariate | P-value | HR multivariate | P-value |
|---|---|---|---|---|---|
| Age at diagnosis, years | 1.01 (0.98;1.03) | 0.678 | 1.01 (0.97; 1.04) | 0.678 | |
| Sex | |||||
| Female | 3.75 (2.96; 5.49) | Ref. | Ref. | ||
| Male | 4.01 (3.38; 5.68) | 0.84 (0.56; 1.26) | 0.399 | 0.68 (0.40; 1.13) | 0.396 |
| Oxaliplatin retreatment line | |||||
| Third line | 4.53 (3.22; 5.78) | Ref. | Ref | ||
| Fourth line | 3.68 (2.96; 4.37) | 1.31 (0.84; 2.04) | 0.237 | 1.16 (0.69; 1.9) | 0.240 |
| Tumor location | |||||
| Left | 4.53 (3.94; 5.78) | Ref. | Ref. | ||
| Right | 3.06 (2.07; 4.01) | 1.87 (1.16; 3.01) | 0.01 | 1.72 (0.98; 3.01) | 0.009 |
| Mutation status | |||||
| Mutated | 3.63 (2.73; 4.11) | Ref. | Ref. | ||
| Wild-type | 5.68 (3.68; 7.95) | 0.70 (0.45; 1.08) | 0.108 | 0.92 (0.55; 1.51) | 0.108 |
| Oxaliplatin-free interval (median) | |||||
| > median (17.2 months) | 4.21 (3.68; 7.82) | Ref. | Ref. | ||
| ≤ median (17.2 months) | 3.75 (2.53; 5.03) | 1.45 (0.96; 2.20) | 0.079 | 1.56 (0.94; 2.55) | 0.076 |
| First-line responder | |||||
| No | 2.30 (1.45; NR) | Ref. | Ref. | ||
| Yes | 4.01 (3.68; 5.49) | 0.71 (0.32; 1.55) | 0.386 | 1.57 (0.56; 4.37) | 0.390 |
| Bevacizumab history | |||||
| NB/B | 6.47 (4.11; 9.23) | Ref. | |||
| B/B | 4.30 (3.68; 8.28) | 1.6 (0.61; 0.88) | 0.01 | 2.38 (1.13; 5.00) | 0.022 |
| B/NB | 2.87 (2.07; 4.01) | 3.8 (0.26; 2.02) | <0.001 | 4.62 (2.21; 9.63) | <0.001 |
| NB/NB | 2.96 (2.00; 5.49) | 1.8 (0.54; 1.10) | 0.02 | 1.82 (1.04; 3.21) | 0.037 |
| Reason for stopping first-line oxaliplatin | |||||
| Planning | 5.03 (4.01; 7.29) | Ref. | Ref. | ||
| Progression | 3.27 (1.84; 9.46) | 1.55 (0.89; 2.70) | 0.123 | 1.59 (0.77; 3.26) | |
| Toxicity | 3.15 (2.30; 4.37) | 1.61 (1.00; 2.61) | 0.051 | 1.83 (1.04; 3.20) | 0.095 |
B, population who received bevacizumab; HR, hazard ratio; NB, population who did not receive bevacizumab; NR, not reached; PFS, progression-free survival; Ref, reference.
In our cohort, oxaliplatin retreatment in the third- or fourth-line setting for mCRC was well-tolerated. Toxicity data were not systematically collected, but based on clinical records, no major toxicities were observed.
Best-responders to oxaliplatin retreatment
Within the cohort of patients with oxaliplatin retreatment, 28 patients (27%) were considered best-responders with median PFS >6 months with retreatment (range 6.6-14.2 months). Median age in this subgroup was 57 years (IQR 39-74 years), 61% were male, 89% had left-sided disease, and 79% had MSS tumors. RAS mutations were identified in 43% of patients. Response in first-line setting was reported in 89% of these patients, 68% had stopped oxaliplatin as part of the planned therapy management, and 75% received bevacizumab in the oxaliplatin retreatment setting (Table 3).
Table 3.
Baseline patient and disease characteristics for the best-responders subgroup
| Variable | Patients, n (%) N = 28 |
|---|---|
| Median age (IQR), years | 57 (39-74) |
| Sex | |
| Female | 11 (39) |
| Male | 17 (61) |
| Tumor location | |
| Left | 25 (89) |
| Right | 3 (11) |
| Stage at diagnosis | |
| I | 1 (4) |
| II | 3 (11) |
| III | 2 (7) |
| IV | 22 (79) |
| MSI status | |
| MSS | 22 (79) |
| Unknown | 6 (21) |
| KRAS status | |
| Mutated | 11 (39) |
| Wild-type | 16 (57) |
| NRAS status | |
| Mutated | 1 (4) |
| Wild-type | 23 (82) |
| First-line responder | |
| Responder | 25 (89) |
| Non-responder | 2 (7) |
| Reason for stopping first-line oxaliplatin | |
| Planned | 19 (68) |
| Toxicity | 5 (18) |
| Disease progression | 4 (14) |
| Oxaliplatin retreatment line | |
| Third line | 23 (82) |
| Fourth line | 5 (18) |
| Bevacizumab retreatment line | |
| Yes | 21 (75) |
| No | 7 (25) |
IQR, interquartile range; MSI, microsatellite instability; MSS, microsatellite stable.
Data for prognostic characteristics and molecular alterations were available for 19 of the best-responders. Of them, 47% were classified as poor prognosis characteristics, 26% as good prognosis, and 26% as best prognosis. The most prevalent molecular alterations were identified in APC (68%), TP53 (63%), RAS (47%), and PIK3CA (21%). Concomitant mutations in APC and TP53 were detected in 47.4% of patients. No significant associations between prognostic characteristics and molecular alterations were observed in the multivariable Cox model analysis (Figure 2).
Figure 2.
Waterfall plot showing progression-free survival (PFS) for the best-responders’ group and molecular alterations (n = 19), according to prognosis. BPC, best prognostic characteristics; GPC, good prognostic characteristics; PPC, poor prognostic characteristic.
Discussion
Our study supports oxaliplatin-based retreatment as a viable therapeutic option from the third line onward for patients with refractory mCRC. Patients re-exposed to oxaliplatin showed a median PFS of 4.0 months and an ORR of 12%, with 27% of the cohort classified as best-responders (PFS >6 months). The treatment showed optimal efficacy in patients who received bevacizumab during retreatment or had a long oxaliplatin-free interval. Among the best-responders, most had previously responded to first-line oxaliplatin, with planned discontinuation. Left-sided tumors presented better PFS in the multivariate analysis. These factors may help identify patients who are more likely to benefit from oxaliplatin retreatment.
Our results align with previously reported findings. The phase II RE-OPEN study on oxaliplatin reintroduction showed an ORR of 6.1% (95% CI 2.5% to 14.7%), a DCR of 39.4% (95% CI 21.8% to 57.0%), and a median PFS of ∼3.3 months.11 Similarly, the phase II randomized ORION study compared biweekly versus standard triweekly XELOX regimens for oxaliplatin reintroduction in third- or later-line therapy. While there were no differences in time-to-treatment failure or OS, the triweekly regimen showed a slightly better PFS (12.1 versus 4.3 months), though not statistically significant (HR 0.672, P = 0.836), and a DCR of 66%.12 The recent retrospective RETROX-CRC study reported a median PFS of 5.1 months (95% CI 4.3-6.1 months) and an ORR of 21.6%.13 A large systematic review further confirmed the variability in outcomes, with DCR ranging from 39% to 79%, median PFS between 3 and 7 months, and ORR between 15% and 20% for oxaliplatin rechallenge.4 In Table 4, we summarize these trials, providing comparative outcomes across different studies on oxaliplatin retreatment.
Table 4.
Studies evaluating oxaliplatin retreatment
| Study | Study type | Retreatment strategy | Patients, n | DCR (%) | ORR (%) | Median PFS (months) | Median OS (months) |
|---|---|---|---|---|---|---|---|
| Current study | Retrospective | Rechallenge Reintroduction |
102 | 39.4 | 12 | 4.0 | 13.5 |
| Suenaga et al. (Re-OPEN)11 | Phase II | Reintroduction | 33 | 39.4 | 6.1 | 3.8 | 9.2 |
| Matsuda et al. (ORION)12 | Phase II | Reintroduction | 46 | 66 | NA | 4.3 | 12.9 |
| Amatu et al. (RETROX)13 | Phase III | Rechallenge Reintroduction |
119 | 57.8 | 21.6 | 5.1 | NA |
| Bazarbashi et al.25 | Retrospective | Rechallenge | 18 | NA | NA | 3.1 | 21.2 |
DCR, disease control rate; NA, not available; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
Treatment options for patients with refractory mCRC have expanded significantly in recent years. Regorafenib demonstrated efficacy in terms of OS and PFS in the CORRECT trial, with OS of 6.4 months and PFS of 1.9 months compared with best supportive care.15 In the phase III RECOURSE trial, TAS-102 showed significant improvements in OS (9.3 months, HR 0.46, P < 0.0001) and PFS (3.3 months, HR 0.56, P < 0.0001).16 In the phase III SUNLIGHT trial, TAS-102 combined with bevacizumab resulted in better outcomes in OS (10.8 months, HR 0.61, P < 0.001) and PFS (5.6 months, HR 0.44, P < 0.001) compared with TAS-102 alone, with an ORR of 6.3% versus 0.9%, respectively (P = 0.004).19 The phase III FRESCO-2 study included patients who had progressed on or were intolerant to TAS-102 and/or regorafenib. In this study, patients were randomly assigned to fruquintinib or placebo, with the experimental arm showing improved OS (7.4 months, HR 0.66, P < 0.0001) and PFS (3.7 months, HR 0.32, P < 0.001).17 In RAS wild-type tumors, the CRICKET and CHRONOS trials evaluated the rechallenge strategy with anti-EGFR therapy, demonstrating an ORR ranging from 25% to 30%, with PFS ranging from 4 to 4.8 months.20,21
The improved PFS in left-sided tumors may reflect either a specific benefit from oxaliplatin rechallenge or the inherently better prognosis of left-sided colorectal cancer.22,23 Similarly, the association between bevacizumab use and improved outcomes in our cohort is consistent with its well-established efficacy across multiple treatment lines in mCRC.16,24 Interestingly, clinical prognostic models failed to consistently predict PFS in our retreatment population (Figure 2), suggesting that in the refractory setting, traditional risk stratification may have limited value. Instead, molecular features (e.g. RAS/BRAF mutations, MSI status), prior treatment response, oxaliplatin-free interval, and concurrent use of targeted agents may more accurately influence outcomes. These findings highlight the importance of incorporating molecular and treatment-related factors into decision-making for heavily pretreated patients.
Few studies directly compare chemotherapy retreatment with new therapeutic strategies. Recently, data from a retrospective study including 132 patients with mCRC in the third-line setting were reported. Of these, 29 patients received retreatment with the same chemotherapy regimen they had been initially treated with (62.1% oxaliplatin-based and 37.9% irinotecan-based), whereas 103 patients received regorafenib (60.2%) or FTD/TPI (39.8%). Chemotherapy retreatment resulted in a median PFS of 3.1 months (95% CI 2.6-3.7 months) and a median OS of 21.2 months (95% CI 17.3-25.1 months), compared with 2.9 months (95% CI 2.3-3.5 months, P = 0.357) for PFS and 12.6 months (95% CI 9.3-15.1 months, P = 0.006) for OS in the FTD/TPI-regorafenib group. Although these data should be interpreted with caution, they highlight the importance of careful patient selection to determine the most appropriate treatment regimen at each point in the disease course.25
With all this growing evidence, defining optimal therapeutic strategies for later lines has become increasingly challenging, particularly in a context marked by a clear funnel effect. As treatment lines progress, the likelihood of patients receiving subsequent therapies steadily decreases: only 53% receive a second-line treatment, 28% reach a third, and just 13% proceed to a fourth.8 Moreover, disparities in access to these new therapies on a global scale can significantly impact the treatment options available to patients. This highlights the critical need for personalized treatment strategies, where the most effective available therapies are selected early based on individual patient characteristics, thereby optimizing outcomes by tailoring treatment sequences to the specific needs of each patient.
Conclusions
In conclusion, our findings align with previously reported data, reinforcing that oxaliplatin-based retreatment is a viable option in mCRC with refractory disease, demonstrating a median PFS of 4 months, an ORR of 12%, and 27% of patients achieving a PFS >6 months. However, optimal patient selection, particularly in the context of a growing array of novel therapeutic strategies, remains critical for maximizing treatment outcomes.
Acknowledgements
The authors thank Sara MacKenzie, PhD, for editorial assistance; RC for data collection and management analyses; FR for statistical analysis and data visualization; and AG to data curation. All the authors had full access to the information of the study and read and approved the final manuscript. Also, we thank all patients of the contributors to this work.
Funding
None declared.
Disclosure
NS is supported by a European Society for Medical Oncology (ESMO) Fellowship. All other authors have declared no conflicts of interest. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s) and do not necessarily reflect those of ESMO.
References
- 1.Cervantes A., Adam R., Roselló S., et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10–32. doi: 10.1016/j.annonc.2022.10.003. [DOI] [PubMed] [Google Scholar]
- 2.Benson A.B., Venook A.P., Adam M., et al. Colon cancer, version 3.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2024;22(2 D) doi: 10.6004/jnccn.2024.0029. [DOI] [PubMed] [Google Scholar]
- 3.Yoshino T., Arnold D., Taniguchi H., et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol. 2018;29(1):44–70. doi: 10.1093/annonc/mdx738. [DOI] [PubMed] [Google Scholar]
- 4.Mauri G., Gori V., Bonazzina E., et al. Oxaliplatin retreatment in metastatic colorectal cancer: systematic review and future research opportunities. Cancer Treat Rev. 2020;91 doi: 10.1016/j.ctrv.2020.102112. [DOI] [PubMed] [Google Scholar]
- 5.Vogel A., Hofheinz R.D., Kubicka S., Arnold D. Treatment decisions in metastatic colorectal cancer – beyond first and second line combination therapies. Cancer Treat Rev. 2017;59:54–60. doi: 10.1016/j.ctrv.2017.04.007. [DOI] [PubMed] [Google Scholar]
- 6.Tonini G., Imperatori M., Vincenzi B., Frezza A.M., Santini D. Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer. J Exp Clin Cancer Res. 2013;32(1):92. doi: 10.1186/1756-9966-32-92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Tournigand C., Cervantes A., Figer A., et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer – a GERCOR study. J Clin Oncol. 2006;24(3):394–400. doi: 10.1200/JCO.2005.03.0106. [DOI] [PubMed] [Google Scholar]
- 8.Sonbol M.B., Mountjoy L.J., Firwana B., et al. The role of maintenance strategies in metastatic colorectal cancer: a systematic review and network meta-analysis of randomized clinical trials. JAMA Oncol. 2020;6(3) doi: 10.1001/jamaoncol.2019.4489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.André T., Tournigand C., Mineur L., et al. Phase II study of an optimized 5-fluorouracil-oxaliplatin strategy (OPTIMOX2) with celecoxib in metastatic colorectal cancer: a GERCOR study. Ann Oncol. 2007;18(1):77–81. doi: 10.1093/annonc/mdl336. [DOI] [PubMed] [Google Scholar]
- 10.Maindrault-Goebel F., Tournigand C., André T., et al. Oxaliplatin reintroduction in patients previously treated with leucovorin, fluorouracil and oxaliplatin for metastatic colorectal cancer. Ann Oncol. 2004;15(8):1210–1214. doi: 10.1093/annonc/mdh305. [DOI] [PubMed] [Google Scholar]
- 11.Suenaga M., Mizunuma N., Matsusaka S., et al. Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study. Drug Des Devel Ther. 2015;9:3099–3108. doi: 10.2147/DDDT.S85567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Matsuda C., Honda M., Tanaka C., et al. Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer—biweekly versus standard triweekly XELOX (The ORION Study) Int J Clin Oncol. 2016;21(3):566–572. doi: 10.1007/s10147-015-0911-7. [DOI] [PubMed] [Google Scholar]
- 13.Amatu A., Mauri G., Tosi F., et al. Efficacy of retreatment with oxaliplatin-based regimens in metastatic colorectal cancer patients: the RETROX-CRC retrospective study. Cancers (Basel) 2022;14(5):1197. doi: 10.3390/cancers14051197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Abrams T.A., Meyer G., Schrag D., Meyerhardt J.A., Moloney J., Fuchs C.S. Chemotherapy usage patterns in a US-wide cohort of patients with metastatic colorectal cancer. J Natl Cancer Inst. 2014;106(2) doi: 10.1093/jnci/djt371. [DOI] [PubMed] [Google Scholar]
- 15.Grothey A., Van Cutsem E., Sobrero A., et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–312. doi: 10.1016/S0140-6736(12)61900-X. [DOI] [PubMed] [Google Scholar]
- 16.Tabernero J., Argiles G., Sobrero A.F., et al. Effect of trifluridine/tipiracil in patients treated in RECOURSE by prognostic factors at baseline: an exploratory analysis. ESMO Open. 2020;5(4) doi: 10.1136/esmoopen-2020-000752. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Dasari A., Lonardi S., Garcia-Carbonero R., et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41–53. doi: 10.1016/S0140-6736(23)00772-9. [DOI] [PubMed] [Google Scholar]
- 18.Cox D.R. Regression models and life-tables. J R Stat Soc Series B Stat Methodol. 1972;34(2):187–202. [Google Scholar]
- 19.Prager G.W., Taieb J., Fakih M., et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388(18):1657–1667. doi: 10.1056/NEJMoa2214963. [DOI] [PubMed] [Google Scholar]
- 20.Sartore-Bianchi A., Pietrantonio F., Lonardi S., et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat Med. 2022;28(8):1612–1618. doi: 10.1038/s41591-022-01886-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Cremolini C., Rossini D., Dell’Aquila E., et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial. JAMA Oncol. 2019;5(3):343–350. doi: 10.1001/jamaoncol.2018.5080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Qi G.X., Zhao R.X., Gao C., Ma Z.Y., Wang S., Xu J. Recent advances and challenges in colorectal cancer: from molecular research to treatment. World J Gastroenterol. 2025;31(21) doi: 10.3748/wjg.v31.i21.106964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Costa T., Nuñez J., Felismino T., Boente L., Mello C. REOX: evaluation of the efficacy of retreatment with an oxaliplatin-containing regimen in metastatic colorectal cancer: a retrospective single-center study. Clin Colorectal Cancer. 2017;16(4):316–323. doi: 10.1016/j.clcc.2017.03.002. [DOI] [PubMed] [Google Scholar]
- 24.Tejpar S., Prenen H., Mazzone M. Overcoming resistance to antiangiogenic therapies. Oncologist. 2012;17(8):1039–1050. doi: 10.1634/theoncologist.2012-0068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Bazarbashi S., Alkhatib R., Aseafan M., et al. Efficacy of chemotherapy rechallenge versus regorafenib or trifluridine/tipiracil in third-line setting of metastatic colorectal cancer: a multicenter retrospective comparative study. JCO Glob Oncol. 2024;10 doi: 10.1200/GO.23.00461. [DOI] [PMC free article] [PubMed] [Google Scholar]